PROJECT SUMMARY/ABSTRACT - OVERALL The Inter-collaborative Radiation Countermeasures (INTERACT) Consortium was assembled for the overall goal of developing safe and effective medical countermeasures (MCM) to mitigate and/or treat the acute, delayed, and long-term consequences of radiation exposure for all subsets of the civilian population in the event of a radiological or nuclear (RadNuc) public health emergency. The biological complexity of multiorgan injury (MOI) and failure associated with acute radiation sickness (ARS) and delayed effects of acute radiation exposure (DEARE) requires a comprehensive, multidisciplinary approach to efficiently identify new targets for therapeutic intervention and to move promising MCMs from the research laboratory to advanced pharmaceutical development and approval under the U.S. Food and Drug Administration?s (FDA) Animal Rule (AR) regulatory pathway. INTERACT, a newly formed University of Maryland School of Medicine (UMSOM)-based Center for Medical Countermeasures against Radiation (CMCR), is a partnership of internationally-recognized investigators from four U.S.-based universities who possess a broad depth of expertise in MCM development, a unique set of animal model platforms, and a common goal of sharing ideas and quality practices to advance the cutting-edge scientific discovery and translational development of MCMs. INTERACT projects are broadly designed around a common theme to promote tissue regeneration through targeting the biological processes involved in cellular degeneration that contribute to the clinical manifestation of ARS/DEARE after prompt exposure to high-doses of total body irradiation (TBI). Candidate MCMs under investigation target key biological mechanisms associated with a radiation-induced accelerated aging process including genomic instability, mitochondrial damage, cellular senescence, and inflammation that leads to the hematopoietic (Project 1) and gastrointestinal subsyndromes of ARS (Projects 2, 3), cutaneous radiation injury (Project 3), and DEARE (Projects 1 and 4). Preliminary datum for each of the MCMs under investigation in Projects 1-4 have shown a significant improvement in survival when administered at least 24 hours post- exposure and strong safety profiles in preclinical, and in some cases clinical trials. To advance MCM development within the framework of the AR regulatory pathway for all subsets of the population, projects are supported by two service cores (Core A- Administrative, Core B- Multispecies Efficacy and Pharmacometric Modeling Core) and two consortium cores (Coordinating Center Core, and the Opportunities Fund Management Core). Core B offers one of, if not the most, comprehensive animal model platforms available for MCM testing within the broader CMCR consortia, and includes rabbit, minipig, and non-human primate models of ARS and/or DEARE. INTERACT is synergistic with other potential Centers by offering capabilities and resources currently unavailable to other sites through data and resource sharing and technology transfer to advance and strengthen the National Institute of Allergy and Infectious Diseases (NIAID)/National Institute of Health (NIH)?s mission to ensure the nation?s preparedness to respond to a radiological or nuclear incident.